Li Shuang, Zhang Jianchao, Fu Wanrong, Cao Jinhua, Li Zhonggen, Tian Xiaoxu, Yang Meng, Zhao Jing, Wang Chuchu, Liu Yangyang, Liu Mengduan, Zhao Xiaoyan, Li Xiaowei, Dong Jianzeng, Qi Yuanming
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Hereditary Cardiovascular Diseases, Zhengzhou 450052, China.
Henan Key Laboratory of Hereditary Cardiovascular Diseases, Zhengzhou 450052, China; Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Cell Rep. 2024 Dec 24;43(12):115065. doi: 10.1016/j.celrep.2024.115065. Epub 2024 Dec 12.
SLC25A3 encodes mitochondrial phosphate carrier (PiC), which is involved in inorganic phosphate transport. Clinical reports have found that most patients with homozygous or complex heterozygous mutations in SLC25A3 exhibit lactic acidosis, cardiac hypertrophy, and premature death. However, the potential molecular mechanisms underlying these associations remain unclear. Using CRISPR-Cas9 technology, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying SLC25A3-knockout (KO) or missense mutations (c.C544T, c.A547G, c.C349T) to elucidate the pathogenic mechanisms of SLC25A3-related hypertrophic cardiomyopathy (HCM) and evaluate potential therapeutic interventions. These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca homeostasis imbalance, and mitochondrial energy metabolism dysfunction. Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca homeostasis imbalance in SLC25A3-KO hiPSC-CMs. Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM.
SLC25A3编码线粒体磷酸盐载体（PiC），其参与无机磷酸盐的转运。临床报告发现，大多数SLC25A3纯合或复合杂合突变患者表现出乳酸性酸中毒、心脏肥大和过早死亡。然而，这些关联背后潜在的分子机制仍不清楚。利用CRISPR-Cas9技术，我们生成了携带SLC25A3基因敲除（KO）或错义突变（c.C544T、c.A547G、c.C349T）的人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs），以阐明SLC25A3相关肥厚型心肌病（HCM）的致病机制，并评估潜在的治疗干预措施。这些SLC25A3-KO或错义突变的hiPSC-CMs重现了与心肌肥大相关的疾病表型，包括舒张功能障碍、钙稳态失衡和线粒体能量代谢功能障碍。进一步的研究表明，在SLC25A3-KO hiPSC-CMs中，糖酵解副产物的积累与钙稳态失衡之间存在潜在联系。最后，我们探讨了线粒体移植在挽救SLC25A3相关HCM方面的潜在治疗意义。
